18 Norsteroids as selectively active estrogens

ABSTRACT

The invention relates to novel 18-norsteroids (gonatrienes) of general formula (I), wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 11 , R 11′ , R 14 , R 15 , R 15′ , R 16 , R 17  and R 17′  have the meaning cited in the description, and to the use of said compounds as pharmaceutical active ingredients. Said compounds exhibit a high affinity in vitro for estrogen receptor preparations of rat prostate and in an estrogen receptor preparation of rat uterus. Said compounds exhibit in vivo preferential activity on bones as compared to the uterus and/or significant activity with regard to stimulating the expression of 5HT2a-receptors and transporter molecules. The invention also relates to the production of said compounds, therapeutic use and galenic form of said compounds contained in the novel compounds of invention. The invention also relates to utilization of steroids based on the gonatriene molecular skeleton in order to treat estrogen deficiency-induced diseases and disorders, in addition to the use of said gonatriene structural component in the total structure of compounds which dissociate to produce enhanced estrogen activity in bone as compared to the uterus

This application claims the benefit of priority of U.S. ProvisionalApplication Ser. No. 60/188,197, filed Mar. 10, 2000, and is a NationalStage of PCT/EP00/10804, filed Nov. 2, 2000.

FIELD OF THE INVENTION

This invention relates to new compounds as pharmaceutical activeingredients, which have in vitro a higher affinity to estrogen receptorpreparations from rat prostates than to estrogen receptor preparationsfrom rat uteri and in vivo a preferential action on bone in comparisonto the uterus, and/or pronounced action relative to the stimulation ofthe expression of 5HT2a-receptors and transporters, their production,their therapeutic use and pharmaceutical dispensing forms that containthe new compounds.

The chemical compounds are novel, steroidal, tissue-selective estrogens.

BACKGROUND OF THE INVENTION

Established estrogen therapies for treatment ofhormone-deficiency-induced symptoms and the protective action ofestrogens on bones, brains, vessels and other organ systems.

The efficiency of estrogens in the treatment ofhormone-deficiency-induced symptoms such as hot flashes, atrophy ofestrogen target organs and incontinence, as well as the successful useof estrogen therapies for prevention of bone mass loss in peri- andpostmenopausal women, is well documented and generally accepted (Gradyet al. 1992, Ann Intern Med 117: 1016-1037). It is also well documentedthat estrogen replacement therapy in postmenopausal women or in womenwith ovarian dysfunction that is caused in some other way reduces therisk of cardiovascular diseases compared to non-estrogen-treated women(Grady et al., loc. cit.).

In addition, more recent studies confirm a protective action ofestrogens against neurodegenerative diseases, such as, e.g., Alzheimer'sdisease (Henderson 1997, Neurology 48 (Suppl 7): S27-S35; Birge 1997,Neurology 48 (Suppl 7): S36-S41), a protective action with respect tobrain functions, such as memory and learning capacity (McEwen et al.1997, Neurology 48 (Suppl 7): S8-S15; Sherwin 1997, Neurology 48 (Suppl7): S21-S26), as well as against hormone-deficiency-induced mood swings(Halbreich 1997, Neurology 48 (Suppl 7): S16-S20).

In addition, estrogen replacement therapy has proven effective relativeto the reduction of the incidence of colorectal carcinoma (Calle, E. F.et al., 1995, J Natl Cancer Inst 87: 517-523).

In conventional estrogen or hormone replacement therapy (=HRT), naturalestrogens, such as estradiol, and conjugated estrogens that consist ofequine urine are used either by themselves or in combination with agestagen. Instead of the natural estrogens, derivatives that areobtained by esterification, such as, e.g., 17β-estradiol-valerate, canalso be used.

Because of the stimulating action of the estrogens that are used on theendometrium, which results in an increase of the risk of endometrialcarcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986-1992),estrogen/gestagen combination preparations are preferably used inhormone replacement therapy. The gestagenic component in theestrogen/gestagen combination avoids hypertrophy of the endometrium, butthe occurrence of undesirable intracyclic menstrual bleeding is alsolinked to the gestagen-containing combination.

Selective estrogens represent a more recent alternative to theestrogen/gestagen combination preparations. Up until now, selectiveestrogens have been defined as those compounds that have anestrogen-like effect on the brain, bones and vascular system, owing totheir antiuterotrophic (i.e., antiestrogenic) partial action, but theydo not have a proliferative effect on the endometrium.

A class of substances that partially meet the desired profile of aselective estrogen are the so-called “Selective Estrogen ReceptorModulators” (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9):531-539). In this case, these are partial agonists of estrogen receptorsubtype ERα′. This substance type is ineffective, however, with respectto the therapy of acute postmenopausal symptoms, such as, e.g., hotflashes. As an example of a SERM, the raloxifene that was recentlyintroduced for the indication of osteoporosis can be mentioned.

Estrogen Receptor Beta (ERβ)

Estrogen receptor β(ERβ) was recently discovered as a second subtype ofthe estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93:5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblayet al. (1997), Molecular Endocrinology 11: 353-365). The expressionpattern of ERβ differs from that of the ERα (Kuiper et al. (1996),Endocrinology 138: 863-870). ERβ thus predominates over ERα in the ratprostate, while ERα predominates over ERβ in the rat uterus. Areas inwhich in each case only one of the two ER-subtypes is expressed wereidentified in the brain (Shugrue et al. (1996), Steroids 61: 678-681; Liet al. (1997), Neuroendocrinology 66:63-67). ERβ is expressed in, i.a.,areas that are considered to be important for cognitive processes and“mood” (Shugrue et al. 1997, J Comparative Neurology 388: 507-525).

The 5HT2a-receptors and the serotonin transporters could be moleculartargets for ERβ in these brain areas (G. Fink & B. E. H. Sumner 1996Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular Brain Research,in press). The neurotransmitter serotonin (5-hydroxytryptamine) isinvolved in the regulation of a considerable number of processes thatcan be impaired in menopause. In particular, the effects of menopause onmoods and cognition are related to the serotonergic system. Estrogenreplacement therapy has proven to be effective with respect to thetreatment of these estrogen-deficiency-induced symptoms, possibly bymodulation of serotonin receptor and transporter expression.

Other organ systems with comparatively higher ERβ-expression comprisethe bones (Onoe, Y. et al., 1997, Endocrinology 138: 4509-4512), thevascular system (Register, T. C.; Adams, M. R. 1998, J. Steroid MolecBiol 64: 187-191), the urogenital tract (Kuiper, G. J. M. et al. 1997,Endocrinology 138: 863-870), the gastrointestinal tract(Campbell-Thopson 1997, BBRC 240: 478-483), as well as the testis(Mosselmann, S. et al. 1996 Febs Lett 392 49-53) including thespermatides (Shugrue et al. 1998, Steroids 63: 498-504). The tissuedistribution suggests that estrogens regulate organ functions via ERβ.The fact that ERβ is functional in this respect also follows by studiesin ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bonemass loss in ERKO-mice, which can be cancelled out by estrogensubstitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine SocietyMeeting New Orleans). Estradiol in the blood vessels of female ERKO micealso-inhibits vascular media and smooth muscle cell proliferation(Iafrati, M. D. et al. 1997, Nature Medicine 3: 545-548). Theseprotective actions of estradiol are carried out in the ERKO mousepresumably via ERβ.

Observations of βERKO mice provide an indication on a function of ERβ inthe prostate and bladder: in the case of older male mice, symptoms ofprostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, ProcNatl Acad Sci 95: 15677-15682). In addition, female ERKO mice (Lubahn,D. B. et al. 1993, Proc Natl Acad Sci 90; 11162-11166) and male ERKOmice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well as femaleβERKO mice (Krege, J. H., 1998) have fertility disorders. Consequently,the important function of estrogens with respect to maintaining testisand ovary functions as well as fertility is confirmed.

It was possible to achieve a selective estrogen action on specifictarget organs by subtype-specific ligands based on the different tissueor organ distribution of the two subtypes of the ERs. Substances with apreference for ERβ compared to ERα in the in vitro receptor binding testwere described by Kuiper et al. (Kuiper et al. (1996), Endocrinology138; 863-870). A selective action of subtype-specific ligands of theestrogen receptor on estrogen-sensitive parameters in vivo was notpreviously shown.

The object of this invention is therefore to prepare compounds that havein vitro a dissociation with respect to the binding to estrogen receptorpreparations from rat prostates and rat uteri and that have in vivo adissociation with respect to bones rather than the uterus action. Thecompounds are to have in vitro a higher affinity to estrogen receptorpreparations from rat prostates than to estrogen receptor preparationsfrom rat uteri and in vivo a higher potency with respect to protectionagainst hormone-deficiency-induced bone mass loss in comparison touterus-stimulating action in the uterus and/or pronounced action withrespect to the stimulation of the expression of the 5HT2a-receptors andtransporters.

In the broader sense, a structure-action relationship, which allows foraccess to compounds that have the above-formulated pharmacologicalprofile of better estrogenic action on bones than on the uterus, is tobe made available by this invention.

According to the invention, the object above is achieved by theprovision of gona-1,3,5(10)-triene derivatives of general formula I′

in which

-   -   R¹ means a halogen atom, a radical R¹⁸— or R¹⁸—O—, whereby R¹⁸        means a hydrogen atom or a straight-chain or branched-chain,        saturated or unsaturated hydrocarbon radical with up to 6 carbon        atoms, a trifluoromethyl group,    -   R² means a halogen atom;        -   a radical R¹⁸— or R¹⁸—O—, whereby R¹⁸ has the meaning that            is indicated under R¹; a group R¹⁹SO₂—O—, in which R¹⁹ is an            R²⁰R²¹N group, whereby R²⁰ and R²¹, independently of one            another, represent a hydrogen atom, a C₁-C₅ alkyl radical, a            group C(O)R²², in which R²² can contain a straight-chain or            branched-chain hydrocarbon radical with up to 12 carbon            atoms, which in addition can contain up to three double            bonds and/or triple bonds, a C₃-C₇ cycloalkyl radical, an            aryl radical or a combination of these structural features,            or, together with the N atom, a polymethylenimino radical            with 4 to 6 C atoms or a morpholino radical;    -   R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹        and R²² in each case in the meaning that is indicated under R¹        and R², whereby in addition an aryl, heteroaryl or aralkyl        radical can stand for R¹⁸;    -   R⁶ and R⁷, independently of one another, mean a hydrogen atom, a        halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹,        and R²² in each case in the meaning that is indicated under R¹        or R², a straight-chain or branched-chain, saturated or        unsaturated, partially or completely halogenated alkyl group        with up to 10 carbon atoms or an optionally substituted aryl,        heteroaryl or aralkyl radical,    -   R⁸ and R⁹, independently of one another, mean a hydrogen atom, a        straight-chain or branched-chain, saturated or unsaturated,        optionally partially or completely halogenated hydrocarbon        radical with up to 10 carbon atoms, a group —X—R¹⁸, in which X        is an oxygen or sulfur atom, and R¹⁸ has the meaning that is        indicated under R¹, a halogen atom, a cyano or rhodano group,    -   R¹¹ means a hydrogen atom, a halogen atom, a group R¹⁸—O—,        R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case in the        meaning that is indicated under R¹ and R², a group —X—R¹⁸, in        which X is an oxygen or sulfur atom, and R¹⁸ has the meaning        that is indicated under R¹, a nitrooxy group, a straight-chain        or branched-chain, saturated or unsaturated, partially or        completely halogenated hydrocarbon radical with up to 10 carbon        atoms or an optionally substituted aryl, heteroaryl or aralkyl        radical, and    -   R^(11′) means a hydrogen atom or    -   R¹¹ and R^(11′) together mean a methylene group,    -   R¹⁴ means a hydrogen atom in α-position or a straight-chain or        branched-chain alkyl, alkenyl or alkinyl group with up to 3        carbon atoms, and.    -   R¹⁵ means a hydrogen atom,    -   or    -   R¹⁴ and R¹⁵ together mean a methylene group that is optionally        halogenated in one or two places;    -   R¹⁵ and R¹⁶, independently of one another, mean a hydrogen atom,        a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹        and R²² in each case in the meaning that is indicated under R¹        or R²;    -   R¹⁷ and R^(17′) mean a hydrogen atom and a halogen atom; a        hydrogen atom and a benzyloxy group; a hydrogen atom and a group        R¹⁹SO²—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²², with        R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated        under R¹ or R²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O—        and a group —O—C(O)R²², in all cases above with R¹⁸, R¹⁹, and        R²² in each case in the meaning that is indicated under R¹ or        R²; or    -   R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ and        R²⁴, independently of one another, represent a hydrogen atom and        a halogen atom, or an oxygen atom;        and

one or more double bonds can be present in positions 6, 7; 7, 8; 9, 11;11, 12; 14, 15 and 15, 16 for the treatment ofestrogen-deficiency-induced diseases and conditions.

The possible substituents at carbon atoms 6, 7, 11, 15, 16, and 17 andthe hydrogen atom at carbon atom 13 can be respectively in α- orβ-position.

According to a variant of the invention, preferably compounds of generalformula I′ are used,

in which

-   -   R¹ means a hydrogen atom or a group R¹⁸—O—, whereby R¹⁸ means a        hydrogen atom or a straight-chain or branched-chain, saturated        or unsaturated hydrocarbon radical with up to 6 carbon atoms,    -   R² means a hydrogen or halogen atom or a hydroxy group,    -   R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹        and R²² in each case in the meaning that is indicated under R¹        or R², whereby in addition an aryl or aralkyl radical can stand        for R¹⁸;    -   R⁶ means a hydrogen atom, a hydroxy group, a group R²² in which        an optionally substituted aryl, heteroaryl or aralkyl radical is        in the meaning that is indicated under R²,

R⁷ means a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or—R²², with R¹⁸, R¹⁹, and R²² in each case in the meaning that isindicated under R¹ and R², a straight-chain or branched-chain, saturatedor unsaturated, partially or completely halogenated alkyl group with upto 10 carbon atoms or an optionally substituted aryl, heteroaryl oraralkyl radical,

-   -   R⁸ and R⁹, independently of one another, mean a hydrogen atom, a        straight-chain or branched-chain, saturated or unsaturated,        optionally partially or completely halogenated hydrocarbon        radical with up to 10 carbon atoms, a group —X—R¹⁸, in which X        is an oxygen or sulfur atom, and R¹⁸ has the meaning that is        indicated under R¹, a halogen atom, a cyano or rhodano group,    -   R¹¹ means a hydrogen atom, a halogen atom, a group —R²² with R²²        in the meaning that is indicated under R², a group —X—R¹⁸, in        which X is a sulfur atom and R¹⁸ has the meaning that is        indicated under R¹, a straight-chain or branched-chain,        saturated or unsaturated, partially or completely halogenated        hydrocarbon radical with up to 10 carbon atoms or an optionally        substituted aryl or heteroaryl radical,    -   R¹⁴ means a hydrogen atom in α-position or a straight-chain or        branched-chain alkinyl group with up to 3 carbon atoms, and    -   R¹⁵ means a hydrogen atom    -   or    -   R¹⁴ and R¹⁵ together mean a methylene group;    -   R¹⁵′ and R¹⁶, independently of one another, mean a hydrogen        atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with        R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated        under R¹ or R²;    -   R¹⁷ and R^(17′) mean a hydrogen atom and a halogen atom; a        hydrogen atom and a benzyloxy group; a hydrogen atom and a group        R¹⁹SO²—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²², with        R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated        under R¹ or R²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O—        and a group —O—C(O)R²², in all cases above with R¹⁸, R¹⁹ and R²²        in each case in the meaning that is indicated under R¹ or R²;        and    -   R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ and        R²⁴, independently of one another, represent a hydrogen atom and        a halogen atom, or an oxygen atom.

Another preferred variant of this invention calls for the use of thosecompounds of general formula I′, in which

-   -   R¹ means a hydrogen atom, a hydroxy group or straight-chain or        branched-chain C₁-C₆ alkyl group,    -   R² means a hydrogen atom or fluorine atom or a hydroxy group,    -   R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹        and R²² in each case in the meaning that is indicated under R¹        or R², whereby in addition an aryl or aralkyl radical can stand        for R¹⁸;    -   R⁶ means a hydrogen atom or a hydroxy group,    -   R⁷ means a hydrogen atom, a fluorine or chlorine atom, a group        R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case in        the meaning that is indicated under R¹ or R², a straight-chain        or branched-chain, saturated or unsaturated, partially or        completely halogenated alkyl group with up to 10 carbon atoms or        an optionally substituted aryl, heteroaryl or aralkyl radical,    -   R⁸ and R⁹, independently of one another, mean a hydrogen atom, a        straight-chain or branched-chain, saturated or unsaturated,        optionally partially or completely halogenated hydrocarbon        radical with up to 10 carbon atoms, a group —X—R¹⁸, in which X        is an oxygen atom, and R¹⁸ has the meaning that is indicated        under R¹, a fluorine or chlorine atom or a cyano group,    -   R¹¹ means a hydrogen atom, a fluorine or chlorine atom, a        saturated, straight-chain or branched-chain C₁-C₆ alkyl group, a        group —X—R¹⁸, in which X is a sulfur atom and R¹⁸ means a        saturated, straight-chain or branched-chain C₁-C₆ alkyl group, a        chloromethyl or chloroethyl group or an optionally-substituted        aryl or heteroaryl radical,    -   R¹⁴ means a hydrogen atom in α-position, and    -   R¹⁵ means a hydrogen atom    -   or    -   R¹⁴ and R¹⁵ together mean a methylene group;    -   R^(15′) and R¹⁶, independently of one another, mean a hydrogen        atom, a fluorine or chlorine atom or a group R¹⁸—O or —R²², with        R¹⁸ and R²² in each case in the meaning that is indicated under        R¹ or R²;    -   R¹⁷ and R^(17′) mean a hydrogen atom and a halogen atom; a        hydrogen atom and a benzyloxy group; a hydrogen atom and a group        R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²², with        R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated        under R¹ or R²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O—        and a group —O—C(O)R²², in all cases above with R¹⁸, R¹⁹ and R²²        in each case in the meaning that is indicated under R¹ or R²;        and    -   R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ and        R²⁴, independently of one another, represent a hydrogen atom and        a halogen atom, or an oxygen atom.

According to another variant, gona-1,3,5(10)-triene derivatives ofgeneral formula I′ are used, in which

R⁶, R⁸, R⁹, R¹⁴, R¹⁵, R^(15′) and R¹⁶ in each case stand for a hydrogenatom, and all other substituents have the meanings that are indicated inclaim 1.

If the gonatriene derivatives of general formula I′ contain additionaldouble bonds in the B-, C- and/or D-ring, then a double bond is presentpreferably in position 7, 8 or in position 11, 12 or two double bondsare present in positions 6, 7 and 8, 9.

Another variant of the invention are gonatriene derivatives of generalformula I′

in which

-   -   R¹⁷ and R^(17′) are a group R¹⁸—O— and a group R¹⁸; a group R¹⁸—        and a group —O—C(O)R²², with R¹⁸ and R²² in each case in the        meaning that is indicated under R¹ or R².

Of these last-mentioned derivatives, in turn those gonatrienederivatives are preferred

in which

-   -   R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a C₁-C₄        alkyl group or C₂-C₄ alkenyl group        and especially preferably those        in which    -   R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a        methyl, ethinyl or prop-1-inyl group.

Additional possible configurations of this invention arise fromsubclaims 2 to 15.

In addition to the above use of the compounds of general formula I′, theinvention also relates to the compounds of general formula I themselves.These are the compounds of general formula I′ excluding the compoundsthat at carbon atoms 13, 3, 17, 9, 15 and 16 have the followingsubstituent combinations (here, the other substituents in generalformula I mean hydrogen in each case) as well as double bonds betweenthe indicated carbon atoms (if no indication is made in the table,hydrogen is on the carbon atom in question):

17 (im Falle von 2 Substituenten an C17 handelt es sich beim nichtangegebenen Doppel- Doppel- 13-H Substtituenten um bindung bindung stehf3 ein H-Atom) 9 15 16 zwischen zwischen β isopropyl- ═O carbonyloxy βOAc (Ac = ═O Acetyl) β OAc α-OH β OAc β-OH β OAc α-OAc β OAc β-OAc β OH═O β OH β-OH β OMe (Me = Methyl) β OH α-OVal β OH β-OVal β OH α-OAc β OHβ-OAc β OH α-OH β OH β-OH β OMe β-OH α-OH β OMe β-OH β-OH β OMe ═O β OMeβ-Ac 8, 9 14, 15 β OMe β-Ac α-OH β OMe β-Ac β-OH β OMe ═O OMe/H  9, 1115, 16 β OMe β-Ac β OMe α-Ac α-OH β OMe α-Ac β-OH β OMe β-Ac α-OH β OMeβ-Ac β-OH β OMe β-OH α-OMe β OMe β-OH β-OMe β OMe α-OH β OMe α-OH βO-n-Bu ═O (Bu = Butyl) β O-n-Bu α-OH β O-n-Bu β-OH β O-n-Bu Ac 16, 17 βVal (Val = α-Val Valerat) β Val β-Val β Val α-OH β Val β-OH β Val β-OH αOAc ═O α OH ═O α OMe ═O α OMe α-OH α OMe p-Cl- Benzoat α OMe ═O  9, 11 αOMe β-OH α OMe β-OAc α OMe α-OAc α OMe α-OH/ α-OH β-Me α OMe ═O OMe/H 9, 11 15, 16 α O-n-Bu ═O α O-n-Bu α-OH α O-n-Bu β-OH[Key to First Table Page:]

13-H steht=13-H is

(im Falle von 2 Substituenten an C17 handelt es sich beim nichtangegebenen Substituenten um ein H-atom)=(In the case of 2 substituentsat C17, if unindicated substituents are an H atom)

Doppelbindung zwischen=double bond between

[Key to Second Table Page:] Valerat=valerate

-   -   Benzoat=benzoate

This group of compounds named in the Table is already known; a selectiveestrogenic action and the use of the known compounds in the context ofthis invention has not yet been described, however.

The already known gonatrienes are in most cases described asintermediates, as estrogens in the conventional sense or for use inanalytical processes.

In the compounds of general formulas I and I′ as well as in partialstructures II and II′ that are described below, a fluorine, chlorine,bromine or iodine atom can always stand for a halogen atom; a fluorineatom is preferred in each case. In particular also a chlorine atom canbe named as substituent for the 11β-position.

In particular, the hydrocarbon radicals, which can be partially orcompletely halogenated, are fluorinated radicals.

The alkoxy groups in the compounds of general formulas I and I′ as wellas in partial structures II and II′ that are described below can contain1 to 6 carbon atoms in each case, whereby methoxy, ethoxy, propoxy,isopropoxy and t-butyloxy groups are preferred.

As representatives of the alkylthio groups, for example, methylthio,ethylthio and trifluoromethylthio groups can be mentioned.

Within the context of this invention, an aryl radical is a phenylradical or a 1- or 2-naphthyl radical; the phenyl radical is preferred.

Unless expressly indicated, aryl always also includes a heteroarylradical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl,the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4-or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or4-pyridazinyl radical.

As substituents for an aryl or heteroaryl radical, for example, amethyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-,trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-,halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-,mono(C₁₋₈ alkyl) or di(C₁₋₈ alkyl)amino can be mentioned, whereby bothalkyl groups are identical or different, di(aralkyl)amino, whereby botharalkyl groups are identical or different.

As representatives of straight-chain or branched-chain hydrocarbonradicals with 1 to at most 12 carbon atoms, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,neopentyl, heptyl, hexyl, decyl, undecyl and dodecyl can be mentioned;methyl, ethyl, propyl and isopropyl are preferred.

As a C₃-C₇ cycloalkyl group, a cyclopropyl, butyl, pentyl, hexyl orheptyl group can be cited.

An aralkyl radical is a radical that contains up to 14, preferably 6 to10, C atoms in the ring, and 1 to 8, preferably 1 to 4, C atoms in thealkyl chain. Thus, as aralkyl radicals, for example, benzyl,phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl,and pyridypropyl can be considered. The rings can be substituted in oneor more places by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NO₂, —N₃, —CN,C₁-C₂₀ alkyl, C₁-C₂₀ acyl, or C₁-C₂₀ acyloxy groups.

The alkyl groups can be partially or completely fluorinated orsubstituted by 1-5 halogen atoms, hydroxy groups or C₁-C₄ alkoxy groups.

With a C₂-C₃ alkenyl radical or C₂-C₃ alkinyl radical, a vinyl or allylradical or an ethinyl, 1- or 2-propinyl radical is meant.

As perfluorinated alkyl groups, for example, trifluoromethyl,pentafluoroethyl and nonafluorobutyl can be mentioned. Representativesof partially fluorinated alkyl groups are, for example,2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl,6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.

Monochloromethylene, monofluoromethylene or difluoromethylene can standfor the halogen-substituted 14,15-methylene group.

Other variants of the invention provide one or more optionallyconjugated double bonds in rings B, C and D of the estratriene skeleton,specifically one or more double bonds in positions 6, 7; 7, 8; 9, 11;11, 12; 14, 15 and 15, 16. In this case, a double bond is preferably inposition 7, 8 or in position 11, 12, or two double bonds are inpositions 6, 7 and 8, 9 (i.e., the naphthalene system is formed togetherwith the aromatic A-ring).

One or both hydroxyl groups at C atoms 3 and 17 can be esterified withan aliphatic, straight-chain or branched-chain, saturated or unsaturatedC₁-C₁₄ mono- or polycarboxylic acid or an aromatic carboxylic acid orwith an α- or β-amino acid.

Suitable as such carboxylic acids for esterification are, for example:

Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyricacid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid,lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylicacid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid.

Esterification with acetic acid, valeric acid or pivalic acid ispreferred.

Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaricacid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacicacid, maleic acid, fumaric acid, muconic acid, citraconic acid, andmesaconic acid.

Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalicacid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid,hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, andisonicotinic acid.

Esterification with benzoic acid is preferred.

As amino acids, the representatives of these classes of substances thatare known sufficiently to one skilled in the art are suitable, forexample, alanine, β-alanine, arginine, cysteine, cystine, glycine,histidine, leucine, isoleucine, phenylalanine, proline, etc.

Esterification with β-alanine is preferred.

According to this invention, the compounds below are preferred:

11β-Fluoro-gona-1,3,5(10)-triene-3,17-diol

11β-chloro-gona-1,3,5(10)-triene-3,17-diol

11β-methyl-gona-1,3,5(10)-triene-3,17-diol

11β-ethyl-gona-1,3,5(10)-triene-3,17-diol

11β-phenyl-gona-1,3,5(10)-triene-3,17-diol

7α-fluoro-gona-1,3,5(10)-triene-3,17-diol

7α-methyl-gona-1,3,5(10)-triene-3,17β-diol

7α-phenyl-gona-1,3,5(10)-triene-3,17β-diol

7α-methyl-gona-1,3,5(10)-triene-3,17-diol

7β-fluoro-gona-1,3,5(10)-triene-3,17-diol

7β-methyl-gona-1,3,5(10)-triene-3,17β-diol

7β-phenyl-gona-1,3,5(10)-triene-3,17β-diol

7β-methyl-gona-1,3,5(10)-triene-3,17-diol

7β-ethyl-gona-1,3,5(10)-triene-3,17β-diol

7β-ethyl-gona-1,3,5(10)-triene-3,17α-diol

7β-ethyl-13α-H-gona-1,3,5(10)-triene-3,17α-diol

2-fluoro-gona-1,3,5(10)-triene-3,17β-diol

17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

11-methylene-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

11β-methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

11β,17α-dimethyl-gona-1,3,5(10)-triene-3,17β-diol

11β,17β-dimethyl-gona-1,3,5(10)-triene-3,17α-diol

13α-H-18-nor-estradiol

18-nor-estriol

11β-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

11β-chloro-gona-1,3,5(10)-triene-1,3,17-triol

11β-methyl-gona-1,3,5(10)-triene-1,3,17-triol

11β-ethyl-gona-1,3,5(10)-triene-1,3,17-triol

11β-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7α-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

7α-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7α-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7α-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7β-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

7β-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7β-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7β-methyl-gona-1,3,5(10)-triene-1,3,17-triol

2-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

17α-(1-propinyl)-gona-1,3,5(10)-triene-1,3,17-triol

11-methylene-17α-(1-propinyl)-gona-1,3,5(10)-triene-1,3,17-triol

11β-methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-1,3,17-triol

11β,17α-dimethyl-gona-1,3,5(10)-triene-1,3,17-triol

11β,17β-dimethyl-gona-1,3,5(10)-triene-1,3,17-triol

Within the context of the aspect of use of the invention, the use of thealready known compound 18-nor-17β-estradiol is preferred in addition tothe new compounds that are listed above.

Another aspect of this invention relates to the use of the structuralpart of formula II (gona-1,3,5(10)-structural part)

as a component of the total structure of compounds that have adissociation in favor of their estrogenic action on bone in comparisonto the uterus.

In addition to the aromatic A-ring, one or more optionally conjugateddouble bonds can be present in the B-, C- and/or D-ring in positions 6,7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16.

The possible substituents in carbon atoms 6, 7, 11, 15, 16, and 17, andthe hydrogen atom in carbon atom 13 can be respectively in α- orβ-position.

This invention preferably relates to those structural parts of generalformula II′

in which radicals R¹ to R¹⁷ have the meanings that are indicated ingeneral formula I.

In addition to the aromatic A-ring, these structural parts can also haveone or more, optionally conjugated, double bonds in the B-, C- and/orD-ring.

The possible substituents at carbon atoms 6, 7, 11, 15, 16, and 17 canin turn be in each case in the α- or β-position, and the hydrogen atomat carbon atom 13 can preferably be in β-position.

The esters of the 18-nor-steroids according to the invention haveadvantages as prodrugs compared to the unesterified active ingredientswith respect to their method of administration, their type of action,strength and duration of action.

The 18-nor-steroid sulfamates according to the invention also havepharmacokinetic and pharmacodynamic advantages. In this respect, effectswere already described in the case of sulfamates that are derived fromestrogens with a 13-methyl group (J. Steroid Biochem. Molec. Biol, 55,395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).

In this patent application, steroids on which thegonatriene-(=18-nor-estratriene) skeleton is based for treatment ofestrogen-receptor β-mediated diseases and conditions are described asselective estrogens, which have in vitro dissociation with respect tobinding to estrogen receptor preparations of rat prostates and rat uteriand which have in vivo dissociation with respect to bone action incomparison to uterus action: the substances act in a bone-protectivemanner over a wide dose range without stimulating the uterus. In thesame dose range, their liver action is small.

In addition, the substances exert estrogen-like action on the vascularsystem and brain functions. Substances with higher binding to the ratprostates—compared to the rat-uterus-estrogen receptor—are more powerfulwith respect to the increase of the expression of the serotoninreceptors and transporters, in comparison to their positive effect onthe LH-release. Processes in which regulation of the neurotransmitterserotonin is involved are therefore influenced advantageously, and thecompounds according to the invention then exert an advantageousinfluence especially on mood and cognition.

They can be used in humans as estrogens in the context described in WO97/45125 for the production of medications for influencing the level ofserotonin or serotonin mRNA.

It has been found that the nor-steroids according to the invention aresuitable as selective estrogens for the treatment of various conditionsand diseases, which are characterized by a higher content of estrogenreceptor β than estrogen receptor α in the corresponding target tissueor organ.

The invention also relates to pharmaceutical preparations that containat least one compound of general formula I (or physiologicallycompatible addition salts with organic and inorganic acids of them) andthe use of the compounds of general formula I′ for the production ofpharmaceutical agents, especially for the indications below.

The compounds can be used for the following indications both after oraland parenteral administration.

The novel selective estrogens that are described in this patent can beused as individual components in pharmaceutical preparations or incombination especially with antiestrogens or gestagens. Especiallypreferred is the combination of selective estrogens with ERα-selectiveantiestrogens, or with antiestrogens that are peripherally-selectivelyactive, i.e., that do not pass through the blood-brain barriers.

The substances and the pharmaceutical agents that contain them areespecially suitable for the treatment of peri- and postmenopausalsymptoms, especially hot flashes, sleep disturbances, irritability, moodswings, incontinence, vaginal atrophy, and hormone-deficiency-inducedemotional diseases. The substances for hormone substitution and therapyof hormone-deficiency-induced symptoms in the case of surgical,medicinal or ovarian dysfunction that is caused in some other way arealso suitable. Prevention of bone mass loss in postmenopausal women, inwomen who have undergone hysterectomies or in women who were treatedwith LHRH agonists or LHRH antagonists is also part of this.

The compounds are also suitable for alleviating symptoms of malemenopause and female menopause, i.e., for male and female hormonereplacement therapy (HRT), specifically both for prevention and fortreatment, in addition for treatment of symptoms that are accompanied bya dysmenorrhea as well as for treatment of acne.

In addition, the substances can be used for prophylaxis againsthormone-deficiency-induced bone mass loss and osteoporosis, forprevention of cardiovascular diseases, especially vascular diseases suchas arteriosclerosis, for inhibition of the proliferation of arterialsmooth muscle cells, for treatment of primary pulmonary high bloodpressure and for prevention of hormone-deficiency-inducedneurodegenerative diseases, such as Alzheimer's disease, as well ashormone-deficiency-induced impairment of memory and learning capacity.

In addition, the substances can be used for treatment of inflammatorydiseases and diseases of the immune system, especially auto-immunediseases, such as, e.g., rheumatoid arthritis.

In addition, the compounds can be used for the treatment of malefertility disorders and prostatic diseases.

The compounds can also be used in combination with the natural vitaminD3 or with calcitriol analogues for bone formation or as supportingtherapies to therapies that cause bone mass loss (for example, therapywith glucocorticoids, chemotherapy).

Finally, the compounds of general formula I′ can be used in connectionwith progesterone receptor antagonists, specifically especially for usein hormone replacement therapy and for treatment of gynecologicaldisorders.

A therapeutic product that contains an estrogen and a pure antiestrogenfor simultaneous, sequential or separate use for the selective estrogentherapy of perimenopausal or postmenopausal conditions is alreadydescribed in EP-A 0 346 014.

The amount of a compound of general formula I′ that is to beadministered varies within a wide range and can cover any effectiveamount. On the basis of the condition that is to be treated and the typeof administration, the amount of the compound that is administered canbe 0.01 μg/kg-10 mg/kg of body weight, preferably 0.04 Ag/kg-1 mg/kg ofbody weight, per day.

In humans, this corresponds to a dose of 0.8 μg to 800 mg, preferably3.2 μg to 80 mg, daily.

According to the invention, a dosage unit contains 1.6 μg to 200 mg ofone or more compounds of general formula I.

The compounds according to the invention and the acid addition salts aresuitable for the production of pharmaceutical compositions andpreparations. The pharmaceutical compositions or pharmaceutical agentscontain as active ingredient one or more of the compounds according tothe invention or their acid addition salts, optionally mixed with otherpharmacologically or pharmaceutically active substances. The productionof the pharmaceutical agents is carried out in a known way, whereby theknown and commonly used pharmaceutical adjuvants as well as othercommonly used vehicles and diluents can be used.

As such vehicles and adjuvants, for example, those are suitable that arerecommended or indicated in the following bibliographic references asadjuvants for pharmaceutics, cosmetics and related fields: UllmansEncyklopädie der technischen Chemie [Ullman's Encyclopedia of TechnicalChemistry], Volume 4 (1953), pages 1 to 39; Journal of PharmaceuticalSciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald,Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants forPharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 andff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetikund angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics,Cosmetics and Related Fields], Cantor KG, Aulendorf in Württemberg 1971.

The compounds can be administered orally or parenterally, for exampleintraperitoneally, intramuscularly, subcutaneously or percutaneously.The compounds can also be implanted in the tissue.

For oral administration, capsules, pills, tablets, coated tablets, etc.,are suitable. In addition to the active ingredient, the dosage units cancontain a pharmaceutically compatible vehicle, such as, for example,starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

For parenteral administration, the active ingredients can be dissolvedor suspended in a physiologically compatible diluent. As diluents, veryoften oils with or without the addition of a solubilizer, a surfactant,a suspending agent or an emulsifying agent are used. Examples of oilsthat are used are olive oil, peanut oil, cottonseed oil, soybean oil,castor oil and sesame oil.

The compounds can also be used in the form of a depot injection or animplant preparation, which can be formulated so that a delayed releaseof active ingredient is made possible.

As inert materials, implants can contain, for example, biodegradablepolymers, or synthetic silicones such as, for example, silicone rubber.In addition, for percutaneous administration, the active ingredients canbe added to, for example, a patch.

For the production of intravaginal systems (e.g., vaginal rings) orintrauterine systems (e.g., pessaries, coils, IUDs, mirena®) that areloaded with active compounds of general formula I′ for localadministration, various polymers are suitable, such as, for example,silicone polymers, ethylene vinyl acetate, polyethylene orpolypropylene.

To achieve better bio-availability of the active ingredient, thecompounds can also be formulated as cyclodextrin clathrates. For thispurpose, the compounds are reacted with α-, β-, or γ-cyclodextrin orderivatives of the latter (PCT/EP95/02656).

According to the invention, the compounds of general formula I′ can alsobe encapsulated with liposomes.

Methods

Estrogen Receptor Binding Studies

The binding affinity of the new selective estrogens was tested incompetitive experiments with use of 3H-estradiol as a ligand to estrogenreceptor preparations of rat prostates and rat uteri. The preparation ofprostate cytosol and the estrogen receptor test with prostate cytosolwas carried out as described by Testas et al. (1981) (Testas, J. et al.,1981, Endocrinology 109; 1287-1289).

The preparation of rat uterus cytosol, as well as the receptor test withthe ER-containing cytosol were basically performed as described by Stackand Gorski, 1985 (Stack, Gorski 1985, Endocrinology 117, 2024-2032) withsome modifications as described in Fuhrmann et al. (1995) (Fuhrmann, U.et al. 1995, Contraception 51: 45-52).

The substances that are described in this patent have higher bindingaffinity to the estrogen receptor of rat prostates than to estrogenreceptors of rat uteri. In this case, it is assumed that ERβpredominates in the rat prostates over ERα, and ERα predominates in ratuteri over ERβ. Table 1 shows that the ratio of the binding to prostateand uterus receptors qualitatively coincides with the quotient ofrelative binding affinity (RBA) to human ERβ and ERα of rats (accordingto Kuiper et al. (1996), Endocrinology 138: 863-870) (Table 1).

Table 2 shows the results of the compound to be used according to theinvention

18-nor-17β-estradiol (compound A) as well as for the compounds accordingto the invention

11β,17α-dimethyl-gona-1,3,5(10)-triene-3,17β-diol. (compound B),

11-methylene-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol (compoundC),

17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol (compound D) as wellas

11β-methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol (compoundE).

The compounds A, B, C, D and E show a higher binding affinity to theestrogen receptor from the rat prostate than to the estrogen receptorfrom the rat uterus.

In addition, the predictability of the ‘prostate-ER versus the uterus-ERtest system’ was confirmed with respect to tissue-selective action by invivo studies. Substances with a preference for prostate-ER aredissociated in vivo with respect to bone and uterus action in favor ofaction on bones.

Bone Studies

Three-month-old female rats are ovariectomized and treated once dailywith the test compound immediately after the operation for 28 days. Theadministration is carried out subcutaneously in arachis oil/ethanol. Theanimals are sacrificed on the day after the last administration, andtibia as well as uteri are removed. The uteri are weighed, fixed andworked up for histological studies. The determination of bone density iscarried out ex vivo on prepared long bones by means of pQCT(quantitative computer tomography). The measurements are made at adistance of 4-6 mm from the ball of the joint of the proximal tibia.

The ovariectomy reduces the density of the trabecular bone in themeasured area by about 400 mg of Ca²⁺/cm³ to about 300 mg of Ca²⁺/cm³.By treatment with a compound of general formula I according to thisinvention, the degradation of the bone density is prevented orinhibited. The bone density in the proximal tibia was measured.

In considerably smaller amounts, the compounds according to theinvention, which produce a 50% bone protection in comparison to theamounts that produce a 50% uterus stimulation, reflect in vivo thehigher binding affinity to the estrogen receptor of rat prostates thanto the estrogen receptor of rat uteri, relative to the bone mass loss,which can be measured in ovariectomized, untreated female rats 28 daysafter the ovariectomy unlike in intact animals that are subjected tosham operations.

The vascular action of the estrogens according to the invention isdetermined in the model of the ApoE-knockout mouse, as described by R.Elhage et al., 1997 (Elhage, R. et al. 1997, Arteriosclerosis,Thrombosis and Vascular Biology 17: 2679-2684).

To detect the action of estrogens in the brain function, the oxytocinreceptor mRNA expression is used as a surrogate parameter (Hrabovszky,E. et al. 1998, Endocrinology 1339: 2600-2604). Ovariectomized rats aretreated for 7 days with the test substance or vehicle (administration:subcutaneous or oral, six times daily). On day 7 after the firstadministration, the animals are decapitated, the uterus weight isdetermined, and the oxytocin receptor mRNA level is studied by means ofin situ hybridization in suitable brain sections. The ED₅₀ values aredetermined with respect to stimulation of uterus growth and induction ofthe oxytocin receptor mRNA.

Another possibility to detect in vivo the dissociated estrogen action ofthe substances according to the invention consists in that afterone-time administration of the substances in rats, effects on theexpression of the 5HT2a-receptor and serotonin transporter protein andmRNA levels in ERβ-rich brain areas can be measured. Comparable to theeffect on the serotonin receptor and transporter expression, the effecton the LH-secretion is measured. Substances with higher binding to therat prostates—compared to the rat uterus estrogen receptor—are morepowerful with respect to the elevation of the expression of serotoninreceptors and transporters, in comparison to their positive effect onthe LH-release. The density of serotonin receptors and transporters isdetermined in the brain sections by means of radioactive ligands, andthe corresponding mRNA is determined by means of in situ hybridization.The method is described in the literature: G. Fink & B. E. H. Sumner1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular BrainResearch, in press.

In accordance with the stronger binding to rat prostates—in comparisonto the rat uterus-estrogen receptor—substances A, B, C, D and Eaccording to the invention result in an elevated expression of theserotonin receptor and transporter.

Production of the Compounds According to the Invention

For the production of the gonatrienes (=18-nor-estratrienes), twosynthesis strategies are known in the literature:

1. Synthesis according to Coombs and Pinhey: M. M. Coombs, C. W. Vose,J. C. S. Chem. Comm. 1974, 602; J. C. Chapman, J. T. Pinhey, Austr. J.Chem. 1974, 2421; as well as A. Kuhl, H. Karels, W. Kreiser, Helv. Chem.Acta 1999, 30;

2. Synthesis according to Zeelen; M. J. van den Heuvel, C. W. vanBokhoven, H. P. de Jongh, F. J. Zeelen, Recl. Trav. Chim. Pays-Bas 107,1988, 331.

Synthesis According to Zeelen

This synthesis method is suitable for the synthesis of 11β-substituted18-nor-steroids.

According to this method as well as subsequent other functionalizationsat numerous positions of the steroid skeleton, gestagenic18-nor-3-keto-Δ⁴ derivatives with a varied substitution pattern on thesteroid can be obtained according to DE 195 35 851 A1. By subsequentaromatization of the 18-nor-3-keto-Δ⁴ derivatives, compounds of generalformula I according to the invention can be produced. This synthesisroute is suitable in particular for the production of those compounds inwhich the 11-position is substituted. 11-Keto-groups that can beobtained via the 11-hydroxy group or by oxidation from it can besynthesized by functionalization, e.g., by a Wittig reaction, ofnumerous other substituents according to the methods that are known toone skilled in the art.

This process is illustrated by Examples 10 and 11.

According to these examples, the aromatization is carried out withselenium dioxide.

The aromatization can equally be achieved with the microbiologicalprocesses that are known to one skilled in the art.

A type screening yielded that the following microorganisms can performthe reaction:

Bacillus lentus ATCC 13805 Corynebacterium simplex ATCC 6946 Nocardiacorallina ATCC 14350 Nocardia globerula ATCC 9356

The best results can be achieved with the strain Bacillus lentus ATCC13085. This strain was therefore used for the preparative reactions.

Examples 12 to 14 are used for illustration.

The sequence of the reaction steps for the introduction of functionalgroups in the steroid skeleton, for example the introduction of a sidechain at carbon atom 17 by nucleophilic addition, and the aromatizationcan also be reversed.

Synthesis According to Coombs and Pinhey

This synthesis route is set forth below in the example of the productionof the unsubstituted 18-nor-17β-estradiol.

The opening of the D-ring by anomalous Beckmann reaction can beperformed with a yield of about 40%; the total yield of the next twosteps is about 17% in each case. This synthesis method for theproduction of the compounds of general formula I according to theinvention is illustrated in Examples 1 to 9.

According to general formula I, possible substituents can already bepresent in the final form or in the form of a precursor already in thestarting product, a substituted estrone that already corresponds to thedesired end product.

Substituents at carbon atom 7 are introduced according to the processthat is known to one skilled in the art and that is commonly used, forexample, in the field of antiestrogenic active ingredients bycopper-catalyzed 1,6-addition of the substituent or a reactive precursorof it to a 3-keto-Δ^(4,6) compound, and said substituents are optionallyfurther synthesized (EP 0 138 504 B, WO 98/07740, WO 99/33855).

The introduction of a substituent or reactive precursor at carbon atom 7is also possible by nucleophilic addition of the substituent orprecursor to a 6-vinyl sulfone (DE 42 18 743 A1).

In the last two cases mentioned above, 7α- and 7β-substituted compounds,which can be separated by, for example, chromatographic processes, canbe obtained in various portions, independently of the reactants and theselected reaction conditions.

Also according to known processes, 17-substituents are introduced bynucleophilic addition of the desired substituent or a reactive precursorthereof and are optionally further synthesized.

Substituents according to general formula I can also be introduced inthe stage of the 18-nor steroids, however. This can be useful ornecessary especially in the case of repeated substitution of the desiredfinal compound.

For example, an 11α-hydroxy group can be converted into an 11β-fluorineatom according to the process described by vorbrüggen et al.

Functionalizations at carbon atom 2 are possible, for example, byelectrophilic substitution according to prior deprotonation of position2 of the corresponding 3-(2-tetrahydropyranyl) ether or 3-methyl etherwith a lithium base (e.g., methyllithium, butyllithium). Thus, forexample, a fluorine atom can be introduced by reaction of theC—H-activated substrate with a fluorinating reagent such asN-fluoromethanesulfonimide (WO 94/24098).

The introduction of variable substituents in rings B, C and D of thegonatriene skeleton can take place in this case according to the samechemical teaching with which the corresponding estratriene derivativesare produced (see, i.a.: Steroide [Steroids], L. F. Fieser, M. Fieser,Verlag Chemie, Weinheim/Bergstr., 1961; Organic Reactions in SteroidChemistry, J. Fried, J. A. Edwards, Van Nostrand Reinhold Company, NewYork, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistryof Steroids, F. J. Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo,1990). This relates to, for example, the introduction of substituents,such as hydroxyl or alkyloxy groups, alkyl, alkenyl or alkinyl groups orhalogen, especially fluorine.

The 18-nor-steroid-carboxylic acid esters according to the invention areproduced analogously to the esters that are derived from natural steroidactive ingredients (see, e.g., Pharmazeutische Wirkstoffe, Synthesen,Patente, Anwendungen [Pharmaceutical Active Ingredients, Syntheses,Patents, Uses]; A. Kleemann, J. Engel', Georg Thieme Verlag Stuttgart1978, Arzneimittel, Fortschritte [Pharmaceutical Agents, Improvements]1972 to 1985; A. Kleemann, E. Lindner, J. Engel (Editors), VCH 1987, pp.773-814).

The 18-nor-steroid sulfamates according to the invention are availablein a way that is known in the art from the corresponding hydroxysteroids by esterification with sulfamoyl chlorides in the presence of abase (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).Subsequent acylation of the sulfamide group results in the18-nor-steroidal (N-acyl)sulfamates according to the invention for whichpharmacokinetic advantages were already demonstrated in the 13-methylseries (cf. DE 195 40 233 A1).

The regioselective esterification of the polyhydroxylated steroids withN-substituted and N-unsubstituted sulfamoyl chlorides is carried outaccording to partial protection of the hydroxyl groups that are toremain unesterified. Silylethers have proven their value as protectivegroups with selective reactivity that is suitable for this purpose,since the latter are stable under the conditions of the sulfamateformation, and the sulfamate group remains intact when the silyl ethersare cleaved off again in the regeneration of the residual hydroxyl groupstill contained in the molecule (Steroids 61, 710-717 (1996)).

The production of the sulfamates according to the invention with one ormore additional hydroxyl groups in the molecule is also possible in thata start is made from suitable hydroxy steroid ketones. First, dependingon the goal, one or more existing hydroxyl groups are subjected tosulfamoylation. Then, the sulfamate groups optionally can be convertedinto the (N-acyl)sulfamates in question with a desired acyl chloride inthe presence of a base. The oxosulfamates or oxo-(N-acyl)sulfamates thatare now present are converted by reduction into the correspondinghydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717(1996)).

As suitable reducing agents, sodium borohydride and the borane-dimethylsulfide complex are suitable.

The compounds of general formula I according to the invention areproduced as described in the examples. By an analogous procedure usinghomologous reagents in the reagents that are described in the examples,additional compounds of general formula I can be obtained.

Etherification and/or esterification of free hydroxy groups is carriedout according to methods that are common to one skilled in the art.

The compounds according to the invention can be present in carbon atoms6, 7, 11, 13, 15, 16, and 17 as α,β-stereoisomers. In the production ofcompounds according to the described processes, the compounds accumulatein most cases as mixtures of the corresponding α,β-isomers. The mixturescan be separated by, for example, chromatographic processes.

The examples below are used for a more detailed explanation of theinvention:

EXAMPLES Example 1 11β-Fluoro-gona-1,3,5(10)-triene-3,17-diol

1.1 11β-Fluoro-1,3,5(10)-estratrien-3-ol-17-one

43.55 g of 11β-fluoro-4-estren-17-ol-3-one (150 mmol, TetrahedronLetters 1995, 2611) is suspended in 1500 ml of acetonitrile, 50 g ofcopper(II) bromide is added, and it is stirred at room temperature.After 16 hours, additional copper(II) bromide is added in three portions(25 g, 12 g, 6 g) within 6 hours, and finally stirred for another 6hours at room temperature. The reaction mixture is cooled in an icebath, mixed with 500 ml of water and extracted with ethyl acetate. Theorganic phase is mixed with a little methanol, washed with saturatedbicarbonate solution and common salt solution and dried with sodiumsulfate. After concentration by evaporation, the substance crystallizesout, yield 30.8 g (71% of theory), flash point 233-234° C.

1.2 11β-Fluoro-3-mesyloxy-estra-1,3,5(10)-trien-17-one

28.84 g of 11β-fluoro-1,3,5(10)-estratrien-3-ol-17-one (100 mmol) isdissolved in 200 ml of pyridine, cooled in an ice bath, 20 ml ofmethanesulfonic acid chloride is added in drops, and it is stirred for 2hours at room temperature. Then, it is stirred into 2.5 liters of icewater, and after two hours of stirring, it is filtered off. The solidresidue is dissolved in dichloromethane, the solution is shaken out with1N hydrochloric acid, water and saturated common salt solution and driedwith Na₂SO₄. After the solvent is drawn off, the residue is 37 g, andafter crystallization from methanol, 33.6 g of11β-fluoro-3-mesyloxy-estra-1,3,5(10)-trien-17-one (91% of theory),flash point, is obtained.

1.3 11β-Fluoro-3-mesyloxy-17-oximinoestra-1,3,5(10)-triene

This substance is suspended in 500 ml of ethanol, mixed with 20 g ofhydroxylaminohydrochloride and 40 g of anhydrous sodium acetate, and itis refluxed for 2.5 hours. After cooling, it is diluted with ethylacetate, washed with water, saturated bicarbonate solution and commonsalt solution, and the organic phase is dried with sodium sulfate andconcentrated by evaporation. The residue is crystallized from ethanol,yield 31.8 g (91% of theory), flash point.

1.411β-Fluoro-3-mesyloxy-13,17-seco-estra-1,3,5(10),13(18)-tetraene-17-nitrile

2.3 g of 11β-fluoro-3-mesyloxy-17-oximidoestra-1,3,5(10)-triene (6.3mmol) is dissolved in 10 ml of dimethyl sulfoxide and 10 ml of carbontetrachloride, 3.9 g of dicyclohexylcarbodiimide is added, and it iscooled in an ice bath. Then, 0.33 ml of trifluoroacetic acid is added indrops, and it is,stirred for 3 hours, whereby the temperature increasesto +9° C. The reaction mixture is now added to ice water, shaken outthree times with dichloromethane, the organic phase is washed withwater, saturated bicarbonate solution and common salt solution, driedwith sodium sulfate and concentrated by evaporation. The residue of 4.4g is chromatographed on silica gel with a hexane-ethyl acetate mixture,yield 0.79 g (36% of theory) as a colorless oil.

1.513(18)-Epoxy-11β-fluoro-3-mesyloxy-13,17-seco-estra-1,3,5(10)-triene-17-nitrile

256 mg of seconitrile (0.7 mmol) is dissolved in 10 ml ofdichloromethane, 500 mg of m-chloroperbenzoic acid (70%) is added in twoportions, and it is stirred for 20 hours at room temperature. Themixture is washed with 10% potassium iodide solution, 1 molar sodiumdithionite, saturated bicarbonate solution and common salt solution,dried with sodium sulfate and concentrated by evaporation. The residue(280 mg) is chromatographed on silica gel with hexane and ethyl acetate,yield 131 mg (49% of theory) as a colorless oil (isomer mixture).

1.6 11β-Fluoro-3-mesyloxy-gona-1,3,5(10)-trien-17-one

571 mg of the epoxide above (1.5 mmol) is dissolved in 200 ml oftoluene, 1.3 ml of boron trifluoride etherate is added, and it is heatedfor 16 hours to 110° C. After cooling, the mixture is diluted with ethylacetate, washed with saturated bicarbonate and common salt solution,dried with sodium sulfate and. concentrated by evaporation. The residueof 577 mg is chromatographed on silica gel with hexane and acetone,yield 90 mg (17% of theory) as a solid foam.

1.7 11β-Fluoro-gona-1,3,5(10)-triene-3,17-diol

200 mg of lithium aluminum hydride is added to the solution of 90 mg of11β-fluoro-3-mesyloxy-gona-1,3,5(10)-trien-17-one in 10 ml of anhydrousTHF, and it is stirred for 2 hours while being cooled with ice, for 16hours at room temperature and for 1 hour under reflux. After cooling, itis mixed with saturated common salt solution, extracted with ethylacetate, the organic phase is dried with sodium sulfate, and the solventis concentrated by evaporation. The residue is chromatographed on silicagel with hexane and ethyl acetate, 42 mg of 11β-fluoro-gonadiol (59% oftheory) is isolated as a solid foam.

Example 2 11β-Methyl-gona-1,3,5(10)-triene-3,17-diol

2.1 11β-Methyl-3-mesyloxy-estra-1,3,5(10)-17-one

28.4 g of 11β-methyl-estra-1,3,5(10)-3-ol-17-one (100 mmol, Gantchev, J.Med. Chem 1994, 4164) is converted into the mesylate as described inExample 1.2, yield 33.5 g (92% of theory) as a solid foam.

2.2 11β-Methyl-3-mesyloxy-17-oximinoestra-1,3,5(10)-triene

The production of the oxime is carried out as described in Example 1.3with a yield of 89% (34.0 g), flash point.

2.311β-Methyl-3-mesyloxy-13,17-seco-estra-1,3,5(10),13(18)-tetraene-17-nitrile

The oxime is converted into the seco compound as described in Example1.4, and it accumulates as a solid foam in a yield of 9.1 g (28% oftheory).

2.413(18)-Epoxy-11β-methyl-3-mesyloxy-13,17-seco-estra-1,3,5(10)-triene-17-nitrile

The epoxidation is performed as described in Example 1.5 and yields 6.7g of epoxide (71% of theory) as a colorless oil.

2.5 11β-Methyl-3-mesyloxy-gona-1,3,5(10)-trien-17-one

The gonadiol derivative as described in Example 1.6 is obtained in ayield of 14% of theory (780 mg) by cyclization with boron trifluorideetherate.

2.6 11β-Methyl-gona-1,3,5(10)-triene-3,17-diol

The reduction of the carbonyl group and cleavage of the protective groupwith lithium alanate into the end product (as in Example 1.7) isaccomplished with a yield of 48% (290 mg).

Example 3 11β-Ethyl-gona-1,3,5(10)-triene-3,17-diol

As described in Example 1, the 11β-ethyl-18-nor-estradiol is producedfrom 11β-ethyl-estra-1,3,5(10)-trien-3-ol-17-one (Pomper, J. Med. Chem.1990, 3143) in a total yield of 1.3%, flash point.

Example 4 11β-Phenyl-gona-1,3,5(10)-triene-3,17-diol

In the same way, the corresponding 18-nor compound is produced from11β-phenyl-estra-1,3,5(10)-trien-3-ol-17-one (Tedesco, J. Org. Chem.1995, 5316), total yield 0.7%, flash point.

Example 5 7α-Fluoro-gona-1,3,5(10)-triene-3,17-diol

5.1 3-Benzyloxy-7β-hydroxy-estra-1,3,5(10)-trien-17-one

12.83 g (75 mmol) of benzylbromide is added to a suspension of 20 g(67.74 mmol) of 3,7β-dihydroxy-estra-1,3,5(10)-trien-17-one, 3.55 g(148.23 mmol) of lithium hydroxide in 700 ml of dry dimethylformamide,and it is stirred under an argon atmosphere for 30 minutes at 100° C.For working-up, the reaction solution is poured into tartaric-acid icewater, the precipitated product is suctioned off and dried in air. Thecrude product is taken up in dichloromethane, the organic phase iswashed with water and dried on sodium sulfate. After the solvent isdrawn off in a vacuum, it is chromatographed on silica gel(dichloromethane-ethyl acetate, gradient of up to 3:2), yield 22.81 g(87%).

5.2 3-Benzyloxy-7α-fluoro-estra-1,3,5(10)-trien-17-one

1.50 g (4 mmol) of 7β-alcohol with 1.52 g (10 mmol) of DBU is introducedinto 30 ml of dry toluene, cooled to 0° C. while being stirred and in amoisture-free environment (argon atmosphere), and it is mixed drop bydrop with 1.51 g (5 mmol) of perfluorobutanesulfonic acid fluoride in 10ml of toluene. Then, the ice bath is removed, and it is allowed to stirfor 5 more hours at room temperature. For working-up, it is diluted withethyl acetate (150 ml), the organic phase is washed first with dilutehydrochloric acid, then with sodium hydroxide solution and finally withwater/brine. It is allowed to dry on sodium sulfate, concentrated byevaporation in a vacuum, and the residue is identified with ethylacetate. After concentration by evaporation was again performed, theresidue is chromatographed on silica gel (toluene-ethyl acetate,gradient of up to 95:5), yield 0.35 g (23%).

5.3 3-Benzyloxy-7α-fluoro-gona-1,3,5-trien-17-one

3-Benzyloxy-7α-fluoro-gona-1,3,5(10)-trien-17-one is obtained from 37.8g of 3-benzyloxy-7α-fluoro-estra-1,3,5-trien-17-one as described inExamples 1.2 to 1.6 in a yield of 1.03 g (2.8% of theory) as a solidfoam.

5.4 7α-Fluoro-18-nor-1,3,5(10)-trien3-ol-17-one

0.30 g (0.79 mmol) of benzylated 7α-fluoro-18-nor-estrone is mixed witha mixture that consists of 3 ml of thioanisole and 2 ml oftrifluoroacetic acid, and it is allowed to stand overnight at roomtemperature under a cover gas and in a moisture-free environment. Forworking-up, it is stirred into ice/potassium hydroxide solution,extracted with ethyl acetate, the organic phase is washed neutral anddried on sodium sulfate. The crude product is chromatographed on silicagel (toluene-ethyl acetate, gradient of up to 4:1), yield 0.200 g (87%).

5.5 7α-Fluoro-8-nor-estra-1,3,5(10)-triene-3,17β-diol

0.22 g (0.76 mmol) of 7α-fluoro-18-nor-estrone is dissolved in a mixturethat consists of 3 ml of dichloromethane and 9 ml of methanol, and it ismixed in portions under a cover gas atmosphere at 0° C. with 0.35 g ofsodium borohydride. Then, it is stirred for 30 more minutes at roomtemperature, diluted with dichloromethane (150 ml) and worked up intotartaric acid. The organic phase is dried on sodium sulfate afterwashing with water. The crude product is chromatographed on silica gelafter the solvent is drawn off (toluene-ethyl acetate, gradient of up to1:1), yield 0.22 g (quant.) as a solid foam.

Example 6 7α-Methyl-gona-1,3,5(10)-triene-3,17β-diol

As described in Example 1, 7α-methyl-estra-1,3,5(10)-trien-3-ol-17-one(Ali et al., J. Med. Chem. 1993, 264) is converted into the end productin a yield of 1.8%, flash point.

Example 7 7α-Phenyl-gona-1,3,5(10)-triene-3,17β-diol

7.1 7α-Phenyl-estr-4-ene-3,17-dione

5.76 g of magnesium chips (237 mmol) is suspended in 60 ml of anhydrousTHF, and a total of 36.1 g of bromobenzene (230 mmol), dissolved in 100ml of anhydrous THF, is added slowly and then quickly to start thereaction, and it is heated for 1 hour to 80° C. The mixture of 24 g ofcopper(I) iodide (120 mmol) and 43 g of lithium bromide (480 mmol) in115 ml of anhydrous THL is heated to about 50° C., then 40 ml of DMPU isadded, and it is stirred for 30 minutes. The solution of phenylmagnesiumiodide is cooled to −60° C., and it is slowly mixed with the solution ofthe copper salt. Then, it is kept at −30° C. for 15 minutes, cooledagain to −65° C. and mixed with a solution of 12.4 g ofestra-4,6-diene-3,17-dione (46 mmol) in 115 ml of anhydrous THF. Afterthe last addition, the mixture is allowed to heat to −5° C. within 45minutes, it is cooled again to −40° C., and 15 ml oftrimethylchlorosilane (115 mmol) is added. During the next 45 minutes,the internal temperature increases to −18° C., it is mixed with 15 ml ofglacial acetic acid, the cooling bath is removed, and it is stirred foranother hour. Then, it is diluted with ethyl acetate, washed withsemisaturated ammonium chloride solution, saturated bicarbonate solutionand common salt solution, the organic phase is dried with sodiumsulfate, and the solvent is concentrated by evaporation. The residue ischromatographed on silica gel with hexane, methylene chloride and ethylacetate. The yield of 7α-phenyl-estr-4-ene-3,17-dione is 8.6 g (54% oftheory).

7.2 7α-Phenyl-gona-1,3,5(10)-triene-3,17β-diol

The synthesis sequence is performed as described in Examples 1.1 to 1.7.The yield over all stages is 2.3%.

Example 8 7α-Methyl-gona-1,3,5(10)-triene-1,3,17-triol

8.1 7α-Methyl-estra-1,3,5(10)-triene-1,3-diol-17-one

The solution of 38.4 g ofdiacetoxy-7α-methyl-1,3,5(10)-estra-1,3,5(10)-trien-17-one (100 mmol;Sauer, Chem. Ber. 1982, 459) is dissolved in 300 ml of anhydrousethanol, 30 ml of 4n-NaOH is added, and it is heated for 30 minutes to60° C. Then, the solvent is largely distilled off, the residue is takenup in ethyl acetate and washed neutral with water. The organic phase isdried with sodium sulfate and concentrated by evaporation. The residueis chromatographed on silica gel with benzine-ethyl acetate andcrystallized from ethyl acetate/diisopropyl ether, yield 24 g (80% oftheory), flash point 228-229° C., [α_(−D)]=+209° (0.5% in pyridine).

8.2 7α-Methyl-gona-1,3,5(10)-triene-1,3,17-triol

The synthesis sequence is performed as described in Examples 1.2 to 1.7.The yield over all stages is 4.5%.

Example 9 2-Fluoro-gona-1,3,5(10)-triene-3,17β-diol

9.1 2-Fluoro-3-methoxy-gona-1,3,5(10)-trien-17β-ol

Starting from 30.2 g of 2-fluoro-3-methoxy-estra-1,3,5(10)-trien-17-one(100 mmol, Diorazio, J. C. S. Perkin I 1992, 421), the synthesis of the18-nor compound is performed as described in Examples 1.3 to 1.7, yield5.3%.

9.2 2-Fluoro-gona-1,3,5(10)-triene-3,17-diol

The solution of 0.53 g of 2-fluoro-3-methoxy-gona-1,3,5(10)-trien-17β-olin 50 ml of toluene is mixed with 5 ml of 20% solution of DIBAH intoluene and heated for 2 hours to 80° C. After cooling, water is addeddrop by drop until the reaction has run its course, then it is dispersedbetween water and ethyl acetate, the ethyl acetate phase is washed withconcentrated common salt solution and dried with sodium sulfate. Afterevaporation, a residue remains that is chromatographed on silica gelwith hexane-ethyl acetate, and the yield is 0.32 g (63% of theory).

Example 10 11β,17α-Dimethylgona-1,3,5(10)-triene-3,17β-diol

10.15,6α-Epoxy-3,3-[1,2-ethanediylbis(oxy)]-11-methylene-5α-gonan-17-one

1.4 g (4.45 mmol) of3,3-[1,2-ethanediylbis(oxy)-11-methylenegon-5-en-17-one (for productionsee DE 19535851, Example 2c) is dissolved in 20 ml of dichloromethane.It is mixed with 1.5 ml of saturated aqueous sodium bicarbonatesolution, then cooled to 0° C., and 490 mg (18.3 mmol) of2,2,2-trifluoro-1-(3-nitrophenyl)-ethanone as well as 1.9 ml of hydrogenperoxide (30% aqueous solution, 18.6 mmol) are added at thistemperature. Then, it is stirred for 100 hours at 25° C. Then, 9 ml ofsaturated sodium thiosulfate solution is added to the reaction mixturewhile being cooled slightly. It is extracted with dichloromethane. Theorganic phase is washed with 5% sodium hydroxide solution as well assaturated sodium chloride solution and dried on sodium sulfate. Columnchromatography of the crude product on silica gel with a mixture thatconsists of hexane/ethyl acetate yields 1 g (68%) of 10.1.

¹H-NMR (CDCl₃): d=4.97 (1H), 4.69 (1H), 3.85-4.08 (1H), 3.02 (1H), 2.66(1H) ppm.

10.2 3,3-[1,2-Ethanediylbis(oxy)]-11-methylene-5α-gonane-5,17β-diol

A solution of 1 g (3.03 mmol) of the compound, described under a), in 10ml of tetrahydrofuran is added to a suspension of 990 mg (26 mmol) oflithium aluminum hydride in 20 ml of tetrahydrofuran at 0° C. It isstirred for one more hour at 0° C. and then 20 ml of saturated ammoniumchloride solution is carefully added. The precipitate that forms isfiltered off. The filtrate is diluted with ethyl acetate. The organicphase is then washed with saturated sodium chloride solution and driedon sodium sulfate. Column chromatography of the crude product on silicagel with a mixture that consists of hexane/ethyl acetate yields 980 mg(90%) of 10.2.

¹H-NMR (CDCl₃): δ=4.88 (1H), 4.54 (1H), 3.90-4.06 (4H), 3.84 (1H) ppm.

10.3 3,3-[1,2-Ethanediylbis(oxy)]-11β-methyl-5α-gonane-5,17β-diol

A solution of 980 mg (2.93 mmol) of the compound, described under b), in80 ml of ethanol is mixed with 90 mg of palladium/carbon (10%). It isthen hydrogenated under 1 atmosphere of hydrogen (reaction time about 20minutes). Then, it is filtered on Celite/silica gel and concentrated byevaporation in a vacuum. The crude product that is obtained (986 mg(100%)) is used without purification in the next step.

¹H-NMR (CDCl₃): δ=3.89-4.06 (4H), 3.86 (1H), 3.73 (1H), 0.86 (3H) ppm.

10.4 3,3-[1,2-Ethanediylbis(oxy)]-5-hydrox11β-methyl-5α-gonan-17-one

1.76 g (17.6 mmol) of chromium trioxide is added to 5.9 ml of pyridinein 30 ml of dichloromethane at 0° C. It is allowed to stir for 15 moreminutes at 0° C., and then a solution of 986 mg (2.93 mmol) of thecompound, described under c), in 10 ml of dichloromethane is added. Itis then allowed to stir for one more hour at 0° C., and then washedtwice with 5% aqueous sodium hydroxide solution and once with saturatedaqueous sodium chloride solution. It is dried on sodium sulfate, and thecrude product that is obtained is purified by column chromatography onsilica gel with a mixture that consists of hexane/ethyl acetate. 830 mg(85%) of 10.4 is obtained.

¹H-NMR (CDCl₃): δ=3.92-4.05 (4H), 3.89 (1H), 2.38 (1H), 0.85 (3H) ppm.

10.5 11β,17α-Dimethyl-3,3-[1,2-ethanediylbis(oxy)]-5α-gonane-5,17β-diol(A) and11β,17β-dimethyl-3,3-[1,2-ethanediylbis(oxy)]-5α-gonane-5,17α-diol (B)

A solution of 260 mg (0.78 mmol) of the compound, described under c), ina mixture that consists of 5 ml of tetrahydrofuran and 5 ml of diethylether is added at 0° C. to 4.7 ml of a 1.6 molar solution ofmethyllithium in diethyl ether. It is allowed to stir for one more hourat 0° C., and then the reaction mixture is poured onto saturated aqueousammonium chloride solution. It is extracted with ethyl acetate, theorganic phase is washed with saturated sodium chloride solution anddried on sodium sulfate. The crude product that is obtained is purifiedby column chromatography on silica gel with a mixture that consists ofhexane/ethyl acetate. 166 mg (61%) of compound A and 60 mg (22%) ofcompound B are obtained.

¹H-NMR (CDCl₃):

-   -   Compound A: δ=3.90-4.02 (3H), 2.08 (1H), 1.12 (3H), 0.85 (3H)        ppm.    -   Compound B: δ=3.90-4.03 (3H), 2.12 (1H), 1.28 (3H), 0.85 (3H)        ppm.        10.6 11β,17α-Dimethyl-17β-hydroxy-gon-4-en-3-one

0.4 ml of 4N hydrochloric acid is added to a solution of 166 mg (0.47mmol) of compound A, described under e), in 10 ml of acetone. It isallowed to stir for one more hour at 25° C., and then the reactionmixture is poured onto saturated aqueous sodium bicarbonate solution.Then, it is extracted with dichloromethane. The organic phase is washedwith saturated sodium chloride solution and dried on sodium sulfate. Thecrude product that is obtained is purified by column chromatography onsilica gel with a mixture that consists of hexane/ethyl acetate. 119 mg(87%) of 10.6 is obtained.

¹H-NMR (CDCl₃): δ=5.83 (1H), 1.13 (3H), 0.97 (3H) ppm.

10.7 11β,17α-Dimethylgona-1,3,5(10)-triene-3,17β-diol

Lithium diisopropylamide (LDA) is produced in 10 ml of tetrahydrofuranat 0° C. from 0.77 ml of a 1.6 molar solution of n-butyllithium inhexane (1.23 mmol) and 0.18 ml (1.28 mmol) of diisopropylamine. Then, itis cooled to −78° C., and a solution of 119 mg (0.41 mmol) of thecompound, described under 10.6, in 8 ml of tetrahydrofuran is added. Itis stirred for one more hour at −78° C. Then, 0.16 ml (0.42 mmol) oftrimethylchlorosilane is added. It is allowed to come to 0° C. andstirred for another 30 minutes. Then, the reaction mixture is pouredonto saturated aqueous sodium bicarbonate solution. It is extracted withethyl acetate, the organic phase is washed with saturated aqueous sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The crude silyl enol ether that is obtained(148 mg) is dissolved in 6 ml of acetonitrile. 102 mg (0.45 mmol) ofpalladium(II) acetate is added, and it is allowed to stir for 2.5 morehours at 25° C. Then, the reaction mixture is filtered on Celite, andthe filtrate is concentrated by evaporation in a vacuum. The crudeproduct that is obtained is purified by column chromatography on silicagel with a mixture that consists of hexane/ethyl acetate. 61 mg (52%) ofthe title compound is obtained.

¹H-NMR (CDCl₃): δ=7.04 (1H), 6.58 (1H), 6.47 (1H), 2.60-2.75 (3H), 2.40(1H), 1.14 (3H), 0.72 (3H) ppm.

Example 11 11β,17β-Dimethylgona-1,3,5(10)-triene-3,17α-diol

11.1 11β,17β-Dimethyl-17α-hydroxy-gon-4-en-3-one

Analogously to Example 10.6, 40 mg (81%) of 11.1 is obtained from 60 mg(0.17 mmol) of compound B, described under 10.5, by reaction with 4Nhydrochloric acid in acetone after column chromatography.

¹H-NMR (CDCl₃): δ=5.83 (1H), 1.29 (3H), 0.98 (3H) ppm.

11.2 11β,17β-Dimethylgona-1,3,5(10)-triene-3,17α-diol

Analogously to Example 10.7, 23 mg (57%) of 11.2 is obtained from 40 mg(0.14 mmol) of the compound that is described under 11.1.

¹H-NMR (CDCl₃): δ=7.09 (1H), 6.62 (1H), 6.50 (1H), 2.70-2.85 (3H), 2.48(1H), 1.29 (3H), 0.78 (3H) ppm.

Example 12 11β-Methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

-   -   Substrate amount: 6.0 mg of        17β-hydroxy-11β-methyl-17α-(1-propinyl)-gon-4-en-3-one        -   The production of the title compound with the strain            Bacillus lentus ATCC 13805 is carried out in a 20 ml            fermentation flask.    -   Preculture: 100 ml of sterile medium that consists of 0.5%        glucose, 0.5% yeast extract, 0.1% peptone and 0.2% Coorn steep        liquor. (pH 7.5) is inoculated with a slant culture of the        strain Bacillus lentus ATCC 13805, and it is incubated for 24        hours at 28° C. and 165 rpm in a rotary shaker.    -   Main culture: For biotransformation, 3×20 ml of the preculture        is transferred in each case into one sterile 100 ml shaking        flask. At the same time, the substrate        17β-hydroxy-11β-methyl-17α-(1-propinyl)-gon-4-en-3-one is        dissolved in an organic solvent and added. The concentration in        the culture broth is 100 mg/l. As a solvent, preferably ethanol        is used, but other water-miscible solvents, such as, e.g.,        dimethylformamide, can also be used. The incubation is performed        at 28° C. and 165 rpm in a rotary shaker. The control of the        reaction is carried out with use of methods such as thin-layer        chromatography or preferably HPLC. After 28 hours, the reaction        is completed. The culture broth of the three shaking flasks is        extracted once with 1 volume of methyl isobutyl ketone each, the        organic phases are combined and evaporated to the dry state        under a vacuum.    -   Isolation: The isolation and purification of the reaction        product        11β-methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol are        carried out (because of the small amount) via HPLC under the        following conditions:        -   Column: Semi-prep-column of the Phenomenex Company (LUNA 5μ,            SILICA (2), 250×10 mm),        -   Flow agent: Hexane/dioxane 75/25        -   Flow rate: 5 ml/min    -   Yield: 42%        11β-Methyl-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

Example 1311-Methylene-17α-(1-propinyl)-gona-1,3,5(10)-triene-3,17β-diol

Analogously to Example 12, the title compound is obtained in a yield of90% from 20 mg of17β-hydroxy-11-methylene-17α-(1-propinyl)-gon-4-en-3-one.

Example 4 17α-(1-Propinyl)-gona-1,3,5(10)-triene-3,17β-diol

Analogously to Example 12, the title compound is obtained with a yieldof 40% from 6 mg of 17β-hydroxy-17α-(1-propinyl)-gon-4-en-3-one.

TABLE 1 Rat Rat Prost. Estro- hERα hER β ERβ/ uterus prost. ER/ute- genStructure RBA* RBA* ERα ER (RBA) ER (RBA) rus ER Estra- diol

100 100 1 100 100 1 Es- trone

60 37 0.6 3 2 0.8 17α- Estra- diol

58 11 0.2 2.4 1.3 0.5 Es- triol

14 21 1.5 4 20 5 5-an- dro- stene- diol

6 17 3 0.1 5 50 Geni- steine

5 36 7 0.1 10 100 Cou- mes- trol

94 185 2 1.3 24 18 *Cited from: Kuiper et al. (1996), Endocrinology 138:863-870.

TABLE 2 Compound ER Prostate RBA ER Uterus RBA A 37 3 B 45 26 C 77 4 D10 0.4 E 111 20

1. A gona-1,3,5(10)-triene compound of formula I

in which R¹ means a halogen atom, or R¹⁸—O—, R¹⁸ means a hydrogen atomor a straight-chain or branched-chain, saturated or unsaturatedhydrocarbon radical with up to 6 carbon atoms, R² means a hydrogen atomR¹⁹ is an R²⁰R²¹N group, R²⁰ and R²¹, independently of one another,represent a hydrogen atom, a C₁-C₅ alkyl radical, a group C(O)R²², R²²can contain a straight-chain or branched-chain hydrocarbon radical withup to 12 carbon atoms, which in addition can contain up to three doublebonds and/or triple bonds, a C₃-C₇ cycloalkyl radical, an aryl radicalor a combination of these structural features, or, together with the Natom, a polymethylenimino radical with 4 to 6 C atoms or a morpholinoradical; R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², or an —O-aryl—O-heteroaryl or —O-aralkyl radical; R⁶ is hydrogen, R⁷ is a hydrogenatom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², astraight-chain or branched-chain, saturated or unsaturated, partially orcompletely halogenated alkyl group with up to 10 carbon atoms or anoptionally substituted aryl, heteroaryl or aralkyl radical, R⁸ and R⁹are hydrogen, R¹¹ means a hydrogen atom, a halogen atom, a group R¹⁸—O—,R¹⁹SO₂—O— or —R²², a group —X—R¹⁸, a nitrooxy group, a straight-chain orbranched-chain, saturated or unsaturated, partially or completelyhalogenated hydrocarbon radical with up to 10 carbon atoms or anoptionally substituted aryl, heteroaryl or aralkyl radical, X is anoxygen or sulfur atom, R^(11′), R¹⁴, R¹⁵, R^(15′) and R¹⁶ each mean ahydrogen atom, and R¹⁷ and R^(17′) mean a hydrogen atom and a halogenatom; a hydrogen atom and a group R¹⁹SO₂—O—; hydrogen and a group—O—C(O)R²²; or hydrogen and —R¹⁸—O—.
 2. A compound according to claim 1,in which R¹ is a hydroxy group.
 3. A compound according to claim 1, inwhich R⁷ is a hydrogen atom, a fluorine or chlorine atom, a groupR¹⁸—O—, R¹⁹SO₂—O— or —R²², a straight-chain or branched-chain, saturatedor unsaturated, partially or completely halogenated alkyl group with upto 10 carbon atoms or an optionally substituted aryl, heteroaryl oraralkyl radical.
 4. A compound according to claim 1, in which X is ansulfur atom, R¹¹ is a hydrogen atom, a halogen atom, a group —R²², agroup —X—R¹⁸, a straight-chain or branched-chain, saturated orunsaturated, partially or completely halogenated hydrocarbon radicalwith up to 10 carbon atoms or an optionally substituted aryl orheteroaryl radical.
 5. A compound according to claim 1, in which X is ansulfur atom, R¹⁸ is a saturated, straight-chain or branched-chain C₁-C₆alkyl group, R¹¹ is a hydrogen atom, a fluorine or chlorine atom, asaturated, straight-chain or branched-chain C₁-C₆ alkyl group, a group—X—R¹⁸, a chloromethyl or chloroethyl group or an optionally substitutedaryl or heteroaryl radical.
 6. A compound according to claim 1, in whichR¹ means a hydroxy group, R⁷ means a hydrogen atom, a fluorine orchlorine atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², a straight-chain orbranched-chain, saturated or unsaturated, partially or completelyhalogenated alkyl group with up to 10 carbon atoms or an optionallysubstituted aryl, heteroaryl or aralkyl radical, R¹¹ means a hydrogenatom, a fluorine or chlorine atom, a saturated, straight-chain orbranched-chain C₁-C₆ alkyl group, a group —X—R¹⁸, a chloromethyl orchloroethyl group or an optionally substituted aryl or heteroarylradical, X is a sulfur atom, and R¹⁸ means a saturated, straight-chainor branched-chain C₁-C₆ alkyl group.
 7. A compound according to claim 1,in which R¹⁷ and R^(17′) are hydrogen and —R¹⁸—O—; or hydrogen and agroup —O—C(O)R²².
 8. A compound according to claim 1, in which R³ meansa group R¹⁹SO₂—O— or —O—C(O)R²², or an —O-aryl —O-heteroaryl or—O-aralkyl radical.
 9. A compound according to claim 1, in which R¹⁷ andR^(17′) mean a hydrogen atom and a halogen atom; a hydrogen atom and agroup R¹⁹SO₂—O—; or hydrogen and a group —O—C(O)R²².
 10. A compoundwhich is 11β-Fluoro-gona-1,3,5(10)-triene-3,17-diol11β-chloro-gona-1,3,5(10)-triene-3,17-diol11β-methyl-gona-1,3,5(10)-triene-3,17-diol11β-ethyl-gona-1,3,5(10)-triene-3,17-diol11β-phenyl-gona-1,3,5(10)-triene-3,17-diol7α-fluoro-gona-1,3,5(10)-triene-3,17-diol7α-methyl-gona-1,3,5(10)-triene-3,17β-diol7α-phenyl-gona-1,3,5(10)-triene-3,17β-diol7α-methyl-gona-1,3,5(10)-triene-3,17-diol7β-fluoro-gona-1,3,5(10)-triene-3,17-diol7β-methyl-gona-1,3,5(10)-triene-3,17β-diol7βphenyl-gona-1,3,5(10)-triene-3,17β-diol7β-methyl-gona-1,3,5(10)-triene-3,17-diol11β-fluoro-gona-1,3,5(10)-triene-1,3,17-triol11β-chloro-gona-1,3,5(10)-triene-1,3,17-triol11β-methyl-gona-1,3,5(10)-triene-1,3,17-triol11β-ethyl-gona-1,3,5(10)-triene-1,3,17-triol11β-phenyl-gona-1,3,5(10)-triene-1,3,17-triol7α-fluoro-gona-1,3,5(10)-triene-1,3,17-triol7α-methyl-gona-1,3,5(10)-triene-1,3,17-triol7α-phenyl-gona-1,3,5(10)-triene-1,3,17-triol7α-methyl-gona-1,3,5(10)-triene-1,3,17-triol7β-fluoro-gona-1,3,5(10)-triene-1,3,17-triol7β-methyl-gona-1,3,5(10)-triene-1,3,17-triol7β-phenyl-gona-1,3,5(10)-triene-1,3,17-triol7β-methyl-gona-1,3,5(10)-triene-1,3,17-triol or 13α-H-18-nor-estradiol.11. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically compatible vehicle.
 12. A method fortreating an estrogen-deficiency-induced disease or condition in a womanor man, comprising administering to the woman or man a compoundaccording to claim
 1. 13. A method for treating anestrogen-deficiency-induced disease or condition in a woman or man,comprising administering to the woman or man a compound according toclaim
 10. 14. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is a perimenopausal andpostmenopausal symptom.
 15. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is a peri- andpost-male-menopausal symptom.
 16. A method according to claim 14,wherein the estrogen-deficiency-induced disease or condition is hotflashes, sleep disturbances, irritability, mood swings, incontinence,vaginal atrophy or a hormone-deficiency-induced emotional disease.
 17. Amethod according to claim 16, wherein the disease is in the urogenitaltract.
 18. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is a disease of stomachor intestine.
 19. A method according to claim 18, wherein theestrogen-deficiency-induced disease or condition is an ulcer or ahemorrhagic diatheses in the gastrointestinal tract.
 20. A methodaccording to claim 19, wherein the estrogen-deficiency-induced diseaseor condition is neoplasia.
 21. A method according to claim 12, whereinthe estrogen-deficiency-induced disease or condition is maleinfertility, which is treated in-vitro.
 22. A method according to claim12, wherein the estrogen-deficiency-induced disease or condition is maleinfertility, which is treated in-vivo.
 23. A method according to claim12, wherein the estrogen-deficiency-induced disease or condition isfemale infertility, which is treated in-vitro.
 24. A method according toclaim 12, wherein the estrogen-deficiency-induced disease or conditionis female infertility, which is treated in-vivo.
 25. A method accordingto claim 12, wherein the estrogen-deficiency-induced disease orcondition is a disease treated with hormone replacement therapy (HRT).26. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition ishormone-deficiency-induced bone mass loss.
 27. A method according toclaim 26, wherein the estrogen-deficiency-induced disease or conditionis osteoporosis.
 28. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is a cardiovasculardisease.
 29. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is a vascular disease.30. A method according to claim 29, wherein theestrogen-deficiency-induced disease or condition is arteriosclerosis.31. A method according to claim 29, wherein theestrogen-deficiency-induced disease or condition is neointimalhyperplasia.
 32. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is ahormone-deficiency-induced neurodegenerative disease.
 33. A methodaccording to claim 12, wherein the estrogen-deficiency-induced diseaseor condition is a hormone-deficiency-induced impairment of memory andlearning capacity, wherein Alzheimer's disease is optionally alsotreated.
 34. A method according to claim 12, wherein theestrogen-deficiency-induced disease or condition is an inflammatorydisease or a disease of the immune system.
 35. A method according toclaim 12, wherein the estrogen-deficiency-induced disease or conditionis benign prostate hyperplasia (BPH).